Diabetes mellitus is a burdensome, expensive, and increasingly common chronic illness that often leads to disability and death. Many new therapies for diabetes have emerged in recent years, but there continues to be concern and uncertainty regarding their safety and whether there are any incremental long term benefits. Information on these risks and benefits is unlikely to come from clinical trials in the foreseeable future and high quality observational studies of comparative safety and effectiveness are needed. We propose to study diabetes therapies using the Diabetes Epidemiology Cohorts (DEpiC), a national registry of all VA diabetes patients over more than a decade (about 2 million) that was established by our research team. Using up to 15 years of linked longitudinal national data, we will apply previously developed methodologies to compare medications for diabetes patients in terms of their safety and effectiveness. Drug-to-drug comparisons will be made among medications initially prescribed at different points in the course of diabetes treatment. For this proposal, we begin with a focus on the relative short-term and long-term safety of metformin, sulfonylurea, thiazolidinediones, and newer agents as well as a preliminary effectiveness analysis. Specifically we propose to evaluate relative risks of cardiovascular disease events (myocardial infarction, stroke, congestive heart failure) and mortality associated with use of metformin, sulfonylureas (glyburide, glipizide, glimepiride, older agents), and thiazolidinediones (rosigltizone, pioglitzone), by class and by specific drug within class. In addition, we will evaluate risks of various other adverse events associated with diabetes medications, including risk of lactic acidosis associated with metformin use, particularly in patients with early kidney disease or heart failure, risk of hypoglycemia associated with various sulfonylurea agents, risk of fracture associated with thiazolidinedione use, risks of pneumonia associated with sitagliptin use, and risks of pancreatitis and acute kidney injury associated with exenatide use. In addition we will conduct a preliminary analysis to evaluate diabetes medication effectiveness in terms of glycemic control, time to medication augmentation or switching, and effects on incidence and progression of microvascular complications. Health service utilization and costs will be estimated for observed effects of medication adverse events and benefits. For all evaluations, samples and exposure groups will be selected carefully to replicate common clinical decisions in treatment with application of rigorous epidemiologic methods to reduce potential bias and provide valid and meaningful results. One immediate benefit of this study is that it would provide new evidence related to current efforts in the VA to promote use of metformin as the oral agent of choice for most diabetes patients, including many previously considered to be contraindicated, with more limited use of sulfonyurea and newer agents. This research represents a real opportunity to better understand benefits and risks associated with treatments for diabetes and application of its findings should be used rapidly in adjusting policy for safer and more effective prescribing practices.